| ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. | |
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MedLine Citation:
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PMID: 23318439 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Cyclin D1 deregulation is implicated in the genesis of multiple human cancers. Importantly, nuclear cyclin D1 retention during S-phase promotes DNA re-replication and subsequent genomic instability, providing a direct correlation between aberrant cyclin D1/CDK4 activity, transcriptional regulation and double strand DNA break (DSB) induction. Together, these molecular events catalyze the genomic instability necessary for neoplastic transformation. Given that replication-associated DNA damage is central to cyclin D1-driven neoplasia, inactivation of critical checkpoint mediators should augment cyclin D1-dependent tumorigenesis in vivo. To interrogate potential synergy between constitutively nuclear cyclin D1 expression and impaired DSB-induced checkpoint integrity, Ataxia Telangiectasia Mutated (ATM)-deficient mice harboring the Eμ-D1T286A transgene were generated and evaluated for tumor onset. Eμ-D1T286A/ATM-/- mice exhibit dramatically accelerated incidence of both B- and T-cell lymphomas relative to Eμ-D1T286A or ATM-/- control cohorts. Lymphomas exhibit clonal chromosomal alterations distinct from ATM-/- mice, which typically acquire translocations involving the Tcrα/δ locus during V(D)J recombination, and instead harbor alterations at the c-Myc locus. Collectively, these findings reveal an intricate relationship wherein nuclear cyclin D1/CDK4 drives genomic instability in the absence of ATM function and clonal selection of cells harboring alterations within the murine c-Myc locus, ultimately facilitating transformation and tumor formation.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.577. |
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Authors:
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L P Vaites; Z Lian; E K Lee; B Yin; A Demicco; C H Bassing; J A Diehl |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-14 |
Journal Detail:
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Title: Oncogene Volume: - ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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